Host-Derived Matrix Metalloproteinase-13 Activity Promotes Multiple Myeloma-Induced Osteolysis and Reduces Overall Survival.
Host-Derived Matrix Metalloproteinase-13 Activity Promotes Multiple Myeloma-Induced Osteolysis and Reduces Overall Survival.
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DOI：
10.1158/0008-5472.can-20-2705
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发表时间：
2021-05-01
期刊：
影响因子：
11.2
通讯作者：
Lynch CC
中科院分区：
文献类型：
--
作者：
Lo CH;Shay G;McGuire JJ;Li T;Shain KH;Choi JY;Fuerst R;Roush WR;Knapinska AM;Fields GB;Lynch CC
多发性骨髓瘤促进全身性骨骼疾病，这极大地促进了患者的发病率。活化的破骨细胞（OCL）对富含I型胶原的骨基质的再吸收导致释放可驱动疾病进展的隔离生长因子。基质金属蛋白酶-13（MMP-13）是一种胶原酶，主要由间充质基质细胞（MSC）和MSC衍生的成骨细胞在骨骼中表达。对人多发性骨髓瘤标本的组织化学分析也表明，与CD 138+骨髓瘤细胞相比，MMP-13主要定位于间质区室。在这项研究中，我们进一步确定，多发性骨髓瘤诱导MMP-13在骨基质细胞的表达。由于其降解I型胶原的能力，我们研究了骨基质来源的MMP-13是否有助于骨髓瘤的进展。将多发性骨髓瘤细胞接种到野生型或MMP-13裸小鼠中。在独立的体内研究中，与野生型对照相比，MMP-13缺失小鼠表现出显著更高的总体存活率和更低的骨破坏水平。出乎意料的是，未观察到组间I型胶原蛋白加工的差异。离体基质共培养试验显示MMP-13无效破骨细胞的形成和活性降低。来自野生型和MMP-13缺失MSC的可溶性因子的分析揭示了包括CXCL 7在内的各种破骨细胞生成因子的生物利用度降低。CXCL 7被鉴定为一种新的MMP-13底物和破骨细胞生成的调节剂。强调宿主MMP-13催化活性在多发性骨髓瘤进展中的重要性，我们证明了一种新型的高选择性MMP-13抑制剂的体内疗效，该抑制剂为治疗这种不治之症提供了转化机会。
Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type-I-collagen rich bone matrix by activated osteoclasts (OCL) results in the release of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP-13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP-13 largely localizes to the stromal compartment compared to CD138+ myeloma cells. In this study, we further identified that multiple myeloma induces MMP-13 expression in bone stromal cells. Because of its ability to degrade type-I-collagen, we examined whether bone stromal derived MMP-13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild type or MMP-13 null-mice. In independent in vivo studies, MMP-13 null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared to wild type controls. Unexpectedly, no differences in type-I-collagen processing between the groups were observed. Ex vivo stromal co-culture assays showed reduced formation and activity in MMP-13-null osteoclasts. Analysis of soluble factors from wild type and MMP-13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP-13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP-13 catalytic activity in multiple myeloma progression, we demonstrate the in vivo efficacy of a novel and highly-selective MMP-13 inhibitor that provides a translational opportunity for the treatment of this incurable disease.
影响因子：
4.3
作者：
Mosig RA;Martignetti JA
通讯作者：
Martignetti JA
影响因子：
8
作者：
Frieling JS;Shay G;Izumi V;Aherne ST;Saul RG;Budzevich M;Koomen J;Lynch CC
通讯作者：
Lynch CC